Chronic Lymphocytic Leukemia: Role of First-Generation BTK Inhibitors


A brief review of first-line BTK inhibition in chronic lymphocytic leukemia following the advent of ibrutinib, along with considerations for minimal residual disease testing in this setting.


Sonali M. Smith, MD: I’m going to kick off our second module, which is an update on BTK [Bruton tyrosine kinase] inhibitors, and their therapy and application for patients with chronic lymphocytic leukemia [CLL]. Then we will move on to some emerging therapies. To start, why consider BTK inhibition in this disease? It turns out that the B-cell receptor is a tonic survival signal for CLL cells. It has multiple downstream effector kinases that keep the B-cell proliferating and surviving. Blocking BTK, which is part of the B-cell receptor machinery, effectively shuts down B-cell receptor signaling and leads to cell death as well as cell redistribution into the blood. Then eventually patients can enter a state of remission. I’m going to kick this off with a conversation about the very first BTK inhibitor, which is ibrutinib. Now, this drug has been around for a while, and many patients have been on this for 5, 8, or 10 years since it’s been approved. I’m going to ask my colleague, Susan O’Brien, if you can tell us a bit about some of the updates, including the 8-year follow-up?

Susan M. O’Brien, MD: We have now an 8-year follow-up, which makes it the longest follow-up of any small molecule. That’s the RESONATE-2 trial. That was the randomized trial of ibrutinib vs chlorambucil. That led to ibrutinib being the first small molecule approved as frontline therapy for CLL. What we have seen with the 8-year follow-up is really impressive, which is that at 7 years, there is still no median progression-free survival reached in this patient population. What this tells us is that if the patients can tolerate the drug, which most patients can, and they’re able to stay on it for a long time, they have phenomenal remission durations. Not even reaching a median at 7 years is really impressive and certainly better than any chemoimmunotherapy that we have.

Those are phenomenal data, and it’s especially impressive when you think that we’re not really talking about too many morphologic CRs [complete responses], and we’re certainly not talking about MRD [minimal residual disease] undetectability. But if you can keep the drug going, you can get these incredibly durable remissions that really benefit the patients. There were no new safety signals. We do continue to see hypertension, which can be a late adverse effect, and AFib [atrial fibrillation] can also continue to occur later. Most of the earlier adverse effects such as diarrhea, etc, are reduced over time. As I said, there are no new late safety signals at all, so very encouraging data.

Sonali M. Smith, MD: Susan, before I go on, one aspect I didn’t cover was the definition of MRD. Can you make a quick comment for the audience?

Susan M. O’Brien, MD: Sure. MRD is usually referred to as minimal residual disease, and that’s when we’re getting very deep morphologic remissions. We can look at a deeper level, which can be done through a number of techniques, including flow [cytometry] or next-generation sequencing, etc. The standard in most CLL trials is looking at 104, meaning that if a patient is MRD undetectable, we can’t detect 1 cell in about 10,000.

Transcript edited for clarity.

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